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  Use of convertase inhibitors in the treatment of fibrosis and scarringUSPTO Application #: 20060052309Title: Use of convertase inhibitors in the treatment of fibrosis and scarring Abstract: The present invention relates to use of convertase inhibitors for the reduction of scarring during the healing of wounds and also for reducing fibrosis in the treatment of fibrotic conditions. (end of abstract)
Agent: Morrison & Foerster LLP - San Diego, CA, US Inventors: Mark William James Ferguson, Georg Brunner USPTO Applicaton #: 20060052309 - Class: 514017000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 5 Or 6 Peptide Repeating Units In Known Peptide Chain The Patent Description & Claims data below is from USPTO Patent Application 20060052309. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to wound healing and also to regulating fibrosis in the treatment of conditions in which fibrosis is a major mechanism of tissue repair or where excessive fibrosis leads to pathological derangement and malfunctioning of tissue. [0002] Wound healing in adults is a complicated reparative process. The term "wound" as used herein is exemplified by, but not limited to, injuries to the skin. Other types of wound can involve damage, injury or trauma to an internal tissue or organ such as the lung, kidney, heart, gut, tendons or liver. [0003] The healing process in skin wounds typically begins with a haemostatic response initiated by damage to blood vessels in the skin. During this process platelets and a number of factors present in the blood contribute to the formation of a clot that prevents further blood loss. Factors released during this process, particularly by the degranulation of platelets, then cause recruitment of a variety of specialised cells to the site of the wound that are in turn involved in extracellular matrix and basement membrane deposition, angiogenesis, selective protease activity and re-epithelialisation. An important component of the healing process in adult mammals is the stimulation of fibroblasts to generate the extracellular matrix. This extracellular matrix constitutes a major component of the connective tissue that develops to repair the wound area. [0004] The connective tissue that forms during the healing process is often fibrous in nature and commonly forms into a connective tissue scar (a process known as fibrosis). [0005] A scar is an abnormal morphological structure resulting from a previous injury or wound (e.g. an incision, excision or trauma). Scars are composed of a connective tissue which is predominately a matrix of collagen types 1 and 3 and fibronectin. The scar may consist of collagen fibres with an abnormal organisation (as seen in scars of the skin) or it may be an abnormal accumulation of connective tissue (as seen in scars of the central nervous system). Most scars consist of abnormally organised collagen and also excess collagen. In man, in the skin, scars may be depressed below the surface or elevated above the surface of the skin. Hypertrophic scars represent a severe form of normal scarring. They are elevated above the normal surface of the skin and contain excessive collagen arranged in an abnormal pattern. Keloids are another form of pathological scarring in which the scar is not only elevated above the surface of the skin but also extends beyond the boundaries of the original injury. In a keloid there is excessive connective tissue that is organised in an abnormal fashion predominately in whirls of collagenous tissue. There are genetic predispositions to the formation of both hypertrophic scars and keloids. These aberrant forms of scarring are particularly common in Afro-Caribbean and Mongoloid races. [0006] There are many instances where the regulation of scar formation is of primary importance when considering the outcome of wound healing. Examples of such situations are scars of the skin where excessive scarring may be detrimental to tissue function, particularly in contexts where scar contracture occurs (for instance skin burns and wounds that impair flexibility of a joint). The reduction of scarring to the skin when cosmetic considerations are important is also highly desirable. In the skin hypertrophic or keloid scars can cause functional and cosmetic impairment and there is a need to prevent their occurrence. Scarring resulting from skin grafts in both donor sites and from the application of artificial skin can also be problematic and need to be minimised or prevented. [0007] As well as scars of the skin, internal scarring or fibrosis can be highly detrimental and specific examples include: [0008] (i) Within the central nervous system, glial scarring can prevent neuronal reconnection (e.g. following neuro-surgery or penetrating injuries of the brain). [0009] (ii) Scarring in the eye can be detrimental. In the cornea, scarring can result in abnormal opacity and lead to problems with vision or even blindness. In the retina, scarring can cause buckling or retinal detachment and consequently blindness. Scarring following wound healing in operations to relieve pressure in glaucoma (e.g. glaucoma filtration surgery) results in the failure of the surgery whereby the aqueous humour fails to drain and hence the glaucoma returns. [0010] (iii) Scarring in the heart (e.g. following surgery or myocardial infarction) can give rise to abnormal cardiac function. [0011] (iv) Operations involving the abdomen or pelvis often result in adhesion between viscera. For instance, adhesions between elements of the gut and the body wall may form and cause twisting in the bowel loop leading to ischaemia, gangrene and the necessity for emergency treatment (untreated they may even be fatal). Likewise, trauma or incisions to the guts can lead to scarring and scar contracture to strictures which cause occlusion of the lumen of the guts which again can be life threatening. [0012] (v) Scarring in the pelvis in the region of the fallopian tubes can lead to infertility. [0013] (vi) Scarring following injury to muscles can result in abnormal contraction and hence poor muscular function. [0014] (vii) Scarring or fibrosis following injury to tendons and ligaments can result in serious loss of function. [0015] Related to the above is the fact that there are a number of medical conditions known as fibrotic disorders in which excessive fibrosis leads to pathological derangement and malfunctioning of tissue. Fibrotic disorders are characterised by the accumulation of fibrous tissue (predominately collagens) in an abnormal fashion within the tissue. Accumulation of such fibrous tissues may result from a variety of disease processes. These diseases do not necessarily have to be caused by surgery, traumatic injury or wounding. Fibrotic disorders are usually chronic. Examples of fibrotic disorders include cirrhosis of the liver, liver fibrosis, glomerulonephritis, pulmonary fibrosis, scleroderma, myocardial fibrosis, fibrosis following myocardial infarction, central nervous system fibrosis following a stroke or neuro-degenerative disorders (e.g. Alzheimer's Disease), proliferative vitreoretinopathy (PVR), restenosis (for example following angioplasty) and arthritis. There is therefore also a need for medicaments which may be used for the treatment of such conditions by regulating (i.e. preventing, inhibiting or reversing) fibrosis/scarring in these fibrotic disorders. [0016] Whilst the above considerations mainly apply to conditions, disorders or diseases of man it will be appreciated that wound healing, scarring and fibrotic disorders can also be problematic in other animals, particularly veterinary or domestic animals (e.g. horses, cattle, dogs, cats etc). For instance abdominal wounds or adhesions are a major reason for having to put down horses (particularly race horses), as are tendon and ligament damage leading to scarring or fibrosis. [0017] There have been several recent developments in the fields of wound healing, scarring and fibrotic disorders. Some of these developments revolve around the recent understanding that an array of cytokines and growth factors is intimately involved in the repair of wounded tissue. In particular, members of the Transforming Growth Factor .beta. (TGF-.beta.) superfamily have been found to play an important role in wound healing. At least 25 molecules are known to be members of the TGF-.beta. superfamily. These include a number of cytokines such as TGF-.beta.s 1 to 5, the DVR group (e.g. dpp and Vg1), Bone Morphogenetic Proteins, Nodal, Activin and inhibin. [0018] TGF-.beta.s are often secreted from cells in an inactive form known as latent TGF-.beta.. Latent TGF-.beta. consists of an N terminal Latency Associated Peptide (LAP) and the TGF-.beta. and is also referred to as the Small Latent Complex. Additionally the Small Latent Complex can bind to another peptide (derived from a different gene) of variable size called Latent TGF-.beta. Binding Protein (LTBP) in which case the entire complex is known as the Large Latent TGF-.beta. Complex. [0019] Latent TGF-.beta. is activated when the TGF-.beta. is caused to be dissociated from the LAP. This dissociation may be coordinated at a mannose-6-phosphate/Insuin Like Growth Factor II receptor (M6P-R) and involve proteases such as plasmin, the substrates being associated at the cell surface by tissue transglutaminase. Free radicals and reactive oxygen species can also activate TGF-.beta. by causing dissociation from the LAP. [0020] TGF-.beta. (particularly TGF-.beta..sub.1 and TGF-.beta..sub.2) promotes wound healing but is also associated with increased scar formation and fibrosis. Clinical interest in the modulation of TGF-.beta. has been associated with inhibiting its activity in order to reduce scar formation (although this may compromise the rate of wound healing). For instance, WO 92/17206 discloses neutralising agents that inhibit the activity of TGF-.beta..sub.1 and TGF-.beta..sub.2 and are particularly beneficial for reducing scar formation. [0021] Another development involves the use of mannose-6-phosphate for use in treating fibrotic disorders associated with accumulation of extracellular matrix and with elevated levels of Transforming Growth Factors .beta..sub.1 or .beta..sub.2 (GB-A-2,265,310). Mannose-6-phosphate is believed to interfere with the conversion of latent forms of these Transforming Growth Factors into their active form. [0022] Despite such advances there remains a need to continue to develop medicaments that may be used to modulate the healing of wounds, scarring and fibrosis. In particular there is a need for medicaments which do not compromise the rate of wound healing or quality of scar in favour of one or the other. [0023] As discussed more fully below, the invention relates in its broadest aspect to the use of convertase inhibitors for the treatment of wounds. [0024] According to a first aspect of the present invention there is provided the use of a convertase inhibitor in the manufacture of a medicament for reducing scarring during the healing of wounds or reducing fibrosis in the treatment of fibrotic conditions wherein the medicament is topically applied to the site of a wound or fibrotic disorder. [0025] According to a second aspect of the present invention, there is provided a composition comprising a therapeutically effective amount of a convertase inhibitor and a pharmaceutically acceptable vehicle for the treatment of wounds or fibrosis. [0026] According to a third aspect of the present invention, there is provided a method of treating a subject to reduce or prevent scarring during the healing of wounds; or reduce or prevent fibrosis in the treatment of fibrotic conditions comprising topically administering to a subject in need of such treatment a therapeutically effective amount of a convertase inhibitor. [0027] Convertases are a family of Ca.sup.2+-dependant serine proteases, otherwise known as SPCs (subtilisin-like pro-protein convertases; see Dubois et al., 1995, Journ. Biol. Chem., 270(18):10618-10624; Sha, X., et al., 1989, Mol. Endocrinology, 3:1090-1098; Chan, S. J., et al., 1992, Proc. Natl. Acad. Sci. USA 89: 6678-6682; and references therein). The inventors have found that the convertase enzyme furin is particularly involved in the activation of mature latent TGF-.beta. at the site of a wound or fibrotic disorder. Although the inventors do not wish to be bound by any hypothesis they believe that convertase activity is able to indirectly stimulate TGF-.beta. activation by modifying the activity of other enzyme(s) with TGF-.beta. activating properties. The inventors believe that the convertase activity contributing to TGF-.beta. activation initially occurs intracellularly, within the platelet, and then continues extracellularly as the platelet contents are released on de-granulation. Accordingly convertase inhibitors used according to the present invention are believed to modify activity of this enzyme such that TGF-.beta. activation is reduced. [0028] For the purposes of the specification references to intracellular activity should also be taken to encompass activity within the membranes of cell fragments, such as platelets, except where the context requires otherwise. [0029] The inventors believe that the convertases involved in TGF-.beta. activation are furin-like proprotein convertases. Furins comprise a family of seven transmembrane proprotein convertases produced as an inactive precursor. They must be activated intracellularly, and are involved in pre-protein processing in the trans-Golgi network, at the cell surface, extracellularly and in endosomes. Furins have their effect at arginine-containing cleavage sites, the minimal site being Arg-X-X-Arg. Relevant reviews include Molloy et al, 1999; Shapiro et al. 1997 (J. Histochem. Cytochem. 45:3-12) and Pearton et al. 2001 (Experimental Dermatology 10:193-203). [0030] Platelets are a major source of TGF-.beta. in the circulation and release latent TGF-.beta. when the platelet is activated (e.g. in response to injury). During the healing process, various forms of TGF-.beta. are to be found at a wound site or site of a fibrotic disorder. These different forms are active TGF-.beta. (which is in its free form), the small latent complex (TGF-.beta.-latency associated peptide), and the large latent complex (TGF-.beta.-latency associated peptide-latent TGF-.beta. binding protein). The different complexes undergo different fates and perform different roles during the healing process. In particular, the large and small latent complexes are activated by cleaving in order to release active TGF-.beta. whilst the healing process occurs. [0031] The prior art suggests that cleavage of the large and small latent complexes at a wound site is mediated by plasmin. Furthermore, convertases such as furin are believed to be responsible for the intracellular processing of pro-TGF-.beta. within megakaryocytes (which give rise to platelets) in the bone marrow. This processing of pro-TGF-.beta. involves cleavage and folding of the pro-protein to produce the mature form. The mature form produced is not, however, "active" TGF-.beta., and may be associated with the large or small latent complexes. Accordingly convertases have not previously been thought to play a part in the activation of latent TGF-.beta. (such as TGF-.beta. in the small latent complex) from platelets in the blood at a site of a wound or fibrotic disorder. Continue reading... Full patent description for Use of convertase inhibitors in the treatment of fibrosis and scarring Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Use of convertase inhibitors in the treatment of fibrosis and scarring patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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